title: MicroRNA transcriptome profiling in cardiac tissue of hypertrophic cardiomyopathy patients with MYBPC3 mutations.
abstract: Hypertrophic cardiomyopathy (HCM) is predominantly caused by mutations in genes encoding sarcomeric proteins. One of the most frequent affected genes is MYBPC3, which encodes the thick filament protein cardiac myosin binding protein C. Despite the prevalence of HCM, disease pathology and clinical outcome of sarcomeric mutations are largely unknown. We hypothesized that microRNAs (miRNAs) could play a role in the disease process. To determine which miRNAs were changed in expression, miRNA arrays were performed on heart tissue from HCM patients with a MYBPC3 mutation (n=6) and compared with hearts of non-failing donors (n=6). 532 out of 664 analyzed miRNAs were expressed in at least one heart sample. 13 miRNAs were differentially expressed in HCM compared with donors (at p<0.01, fold change ≥ 2). The genomic context of these differentially expressed miRNAs revealed that miR-204 (fold change 2.4 in HCM vs. donor) was located in an intron of the TRPM3 gene, encoding an aspecific cation channel involved in calcium entry. RT-PCR analysis revealed a trend towards TRPM3 upregulation in HCM compared with donor myocardium (fold change 2.3, p=0.078). In silico identification of mRNA targets of differentially expressed miRNAs showed a large proportion of genes involved in cardiac hypertrophy and cardiac beta-adrenergic receptor signaling and we showed reduced phosphorylation of cardiac troponin I in the HCM myocardium when compared with donor. HCM patients with MYBPC3 mutations have a specific miRNA expression profile. Downstream mRNA targets reveal possible involvement in cardiac signaling pathways.
authors.affiliation: Dept. of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Cell and Molecular Physiology, Loyola University of Chicago, Maywood, IL, USA. Electronic address: dkuster@lumc.edu.
authors.forename: Diederik W D
authors.initials: DW
authors.lastname: Kuster
authors.forename: Joyce
authors.initials: J
authors.lastname: Mulders
authors.forename: Folkert J
authors.initials: FJ
authors.lastname: Ten Cate
authors.forename: Michelle
authors.initials: M
authors.lastname: Michels
authors.forename: Cristobal G
authors.initials: CG
authors.lastname: Dos Remedios
authors.forename: Paula A
authors.initials: PA
authors.lastname: da Costa Martins
authors.forename: Jolanda
authors.initials: J
authors.lastname: van der Velden
authors.forename: Cees B M
authors.initials: CB
authors.lastname: Oudejans
mesh_terms: D000328:Adult; D000368:Aged; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D003198:Computer Simulation; D005260:Female; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome / Q000235:genetics*; D019210:Troponin I / Q000378:metabolism; D055815:Young Adult; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D050053:TRPM Cation Channels; D019210:Troponin I; D000099163:Myosin Binding Protein C; C475667:TRPM3 protein, human
keywords: Heart; Hypertrophic cardiomyopathy; MYBPC3; MicroRNA; Profiling; TRPM3